Epitope-Specific Targeting of Tau Aggregates.

Tau 聚集体的表位特异性靶向。

• 批准号: 10187658
• 负责人: Einar M Sigurdsson
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187658
• 关键词: Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Antibody Affinity; Antigens; Attention; Binding; Brain; Cells; Charge; Chimera organism; Clinical Trials; Collaborations; Crystallization; Dementia; Development; Diagnostic; Disease; Disease model; Epitopes; Future; Human; Immunotherapy; Impaired cognition; Mediating; Monoclonal Antibodies; Mus; Mutation; Neuroglia; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phosphoserine; Property; Proteins; Proteomics; Public Health; Reporting; Research; Research Personnel; Site; Structure; Tauopathies; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Universities; Vaccines; antibody engineering; base; beta amyloid pathology; extracellular; improved; insight; interest; mimetics; prevent; programs; protein misfolding; small molecule; tau Proteins; tau aggregation; uptake

Tau immunotherapy for Alzheimer's disease and related tauopathies has advanced from proof-of- concept studies (Sigurdsson, EM, NIH R01AG020197, 2001; Asuni AA et al, J Neurosci, 27, 2007) to clinical trials. Because tau pathology correlates better with the degree of dementia than amyloid-β (Aβ) pathology, it is likely that targeting tau will be more effective than clearing Aβ in the later stages of the disease, when cognitive impairments are evident. Even though a few clinical trials have been initiated after confirmation and extension of the original studies, we have a very limited understanding of the mechanisms involved in antibody-mediated clearance of tau pathology. Some insight has been obtained on which epitopes to target and the mechanism of action but much remains to be clarified. Interestingly, tau antibodies interact with the protein both extra- and intracellularly but the importance of each site for tau clearance is not well defined, and is likely antibody-dependent. Some antibodies are readily taken up into neurons whereas others are not and these differences are likely charge- dependent. As most of tau is found intraneuronally, targeting it there is likely to be more efficacious than only outside neurons. The overall hypothesis of the project is that tau antibodies can slow the progression of tau pathology in humans. The Specific Aims are: 1) To determine how charge, isotype, affinity and size influence antibody efficacy and to clarify the mechanisms involved, and; 2) Antibody engineering based on structural characterization to improve efficacy and for humanization. Towards these aims, we have established collaborations with investigators at our university, who have complementary interests and expertise. The project will focus on antibodies against a key tau epitope, phospho-serine 396,404, which we targeted in our pioneering studies, and it has now been confirmed to be a feasible target by several groups. We will study how charge, isotype, affinity and size influence the efficacy. Furthermore, we will examine how antibody uptake and glial cells influence efficacy, assess proteomic changes associated with antibody- mediated clearance of tau pathology to identify the pathways involved, and engineer the antibodies to clarify mechanisms and improve efficacy. This program should advance our mechanistic understanding of tau immunotherapies and how those can be improved to treat Alzheimer's disease and related tauopathies, with direct relevance to various other protein misfolding disorders.

tau免疫疗法用于阿尔茨海默氏病和相关的tauopathies已从 概念研究（Sigurdsson，EM，NIH R01AG020197，2001; Asuni AA等人，J Neurosci，27，2007） 试验。因为tau病理与淀粉样蛋白（Aβ）病理相比，与痴呆程度更好 当认知时，靶向tau可能比在疾病后期清除Aβ更有效 证明了损害。 即使在确认和扩展原始试验后已经开始了一些临床试验 研究，我们对抗体介导的清除的机制的理解非常有限 tau病理学。已经获得了一些洞察的见解，以靶向靶向机理，但 还有很多待澄清。有趣的是，tau抗体与细胞内的蛋白质相互作用 但是，每个站点对TAU清除的重要性尚未很好地定义，并且可能依赖于抗体。一些 抗体很容易地将神经元放入神经元中，而其他抗体则可能是电荷的 - 很可能是电荷的 - 依赖。由于大多数tau都是胸内神经元的，因此，瞄准它可能比仅比仅仅 外部神经元。 该项目的总体假设是tau抗体可以减慢tau病理的进展 人类。具体目的是：1）确定电荷，同型，亲和力和大小如何影响抗体 效率并阐明所涉及的机制，以及； 2）基于结构的抗体工程 表征提高效率和人性化。针对这些目标，我们已经建立了 与具有完全兴趣和专业知识的大学的调查员合作。 该项目将重点介绍针对关键Tau表位的抗体，磷酸 - 丝氨酸396,404，我们是我们的 在我们的开拓性研究中，有几个小组确认它是可行的目标。 我们将研究电荷，同型，亲和力和大小如何影响效率。此外，我们将研究如何 抗体摄取和神经胶质细胞会影响效率，评估与抗体相关的蛋白质组学变化 介导的tau病理学清除，以识别所涉及的途径，并设计抗体以克服抗体 机制并提高效率。 该计划应提高我们对Tau免疫疗法以及如何的机械理解 可以改进以治疗阿尔茨海默氏病和相关的tauopathies，直接与其他各种相关 蛋白质错误折叠式疾病。